Alzheimer's disease has emerged as the leading cause of age-related dementia, affecting over 5 million people in the United States alone. Unfortunately, current therapies are not very effective. Hence, there is an urgent need to improve our understanding of the mechanisms that drive the development and progression of AD. Impaired clearance of A? along with enhanced inflammation hav emerged as major drivers of AD progression. This project focuses on gaining an understanding of the immune mechanisms that provide protection against both these processes in healthy controls. The majority of the studies that have investigated the role of the innate immune cells have focused on microglia in neuro-inflammation and the clearance of A?. In contrast, there is a scarcity of information about the role played by other innate immune cells, particularly cells in the periphery such as the dendritic cells (DCs). Such knowledge is essential as DCs have a central role in inflammatory responses, and impart a decisive influence on the quality of the adaptive immune T and B lymphocyte responses. We have recently demonstrated that DCs from healthy aged subjects display weak immune/inflammatory response towards Amyloid beta (A?) which does not induce T cell priming. Furthermore, our preliminary studies demonstrate that IgM antibodies against A?, indicative of weak response, are increased in healthy control subjects while IgG antibodies as well as IL-21 associated with a strong inflammatory response are increased in AD patients. This is supported by our data from the 5XFAD mice (AD model) where we observe increased inflammatory responses compared to wild type controls. We therefore hypothesize that healthy aged individuals mount a weak immune response against A? that is protective and facilitates the clearance of A? without inducing damaging levels of inflammation. In contrast, we posit that MCI and AD subjects mount a strong immune response against A? as indicated by the high levels of IgG antibody, enhancing inflammation and aiding AD progression. Our specific aims are to- 1) determine the role of dendritic cells (DCs) in the immune/inflammatory responses in AD; 2) determine the role of IL-21-induced inflammation in the progression of AD; 3) determine the role of B1 cells in reduced IgM antibody levels against A? in AD and investigate whether the IgM antibodies are protective. Successful completion of the studies may lead to identification of new therapeutic intervention strategies for AD as well as identification of biomarkers.